Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10-10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10-10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
COLORS in IBD group investigators, Oxford IBD cohort study investigators, INTERVAL Study, Swiss IBD cohort investigators, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, Humans, Inflammatory Bowel Diseases, Genetic Predisposition to Disease, Risk Factors, Case-Control Studies, Cohort Studies, Pedigree, Age of Onset, Genes, Recessive, Multifactorial Inheritance, Mutation, Mosaicism, Adult, Child, Child, Preschool, Infant, Infant, Newborn, Female, Male, Genetic Variation, Whole Exome Sequencing, Loss of Function Mutation, NADPH Oxidase 2, Primary Immunodeficiency Diseases